Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). We have also demonstrated that interferon-gamma up-regulates the high affinity receptor for IgG (Fc-gamma-RI) on cultured human mast cells and that aggregation of these receptors through IgG leads to mast cell mediator release. Our studies are directed at delineating the signaling pathways initiated by Fc-epsilon-RI and Fc-gamma-RI receptors. The signaling pathways linking the Fc aggregation to human mast cell activation have yet to be delineated. It is now possible to grow human mast cells from a CD34-positive, pluripotent cell population in primary culture with sufficient number and purity to study defined signaling events. Thus, we have been examining specific signaling pathways involved in Fc-epsilon-RI- and Fc-gamma-RI- dependent inflammatory mediator release from human mast cells. The goal is to identify new therapeutic targets in the treatment of allergic diseases.